ABSTRACT
Previously , we demonstrated that the non-antibiotic penicillin derivative TAP7f inhibited melanoma metastasis in vitro and in vivo through the downregulation of ß-catenin and integrin αVß3. As angiogenesis is required for tumor growth and metastasis, we decided to explore the possible antiangiogenic effect of TAP7f. We found that TAP7f inhibited proliferation, migration, tube formation, and actin cytoskeleton organization of human endothelial cells. In a gel plug assay, an in vivo model for angiogenesis, TAP7f also blocked vascular formation induced by fibroblast growth factor 2. Furthermore, when murine B16-F10 melanoma cells pre-treated with TAP7f were injected intradermally in mice, we observed a decrease in the number and thickness of the capillaries surrounding the tumor. Additionally, TAP7f downregulated vascular endothelial growth factor (VEGF) and platelet-derived growth factor-B (PDGF-B) expression in B16-F10 cells and VEGF receptor expression in HMEC-1 endothelial cells. When the antitumor effect of TAP7f was studied in C57BL/6 J mice challenged with B16-F10 melanoma cells, a significant reduction of tumor growth was observed. Furthermore, a decreased expression of VEGF, PDGF-B, and the endothelial cell marker CD34 was observed in tumors from TAP7f-treated mice. Together, our results suggest that the antiangiogenic activity of TAP7f contributes to its antitumor and antimetastatic action and positions this penicillin derivative as an alternative or complementary agent for the treatment of melanoma. KEY MESSAGES: ⢠TAP7f inhibits proliferation, migration, tube formation, and actin cytoskeleton organization of endothelial cells. ⢠TAP7f downregulates VEGF receptor expression in endothelial cells. ⢠TAP7f downregulates VEGF and PDGF expression in melanoma cells. ⢠TAP7f inhibits angiogenesis in vivo.
Subject(s)
Melanoma, Experimental , Vascular Endothelial Growth Factor A , Mice , Humans , Animals , Vascular Endothelial Growth Factor A/metabolism , Endothelial Cells/metabolism , Penicillins/pharmacology , Penicillins/therapeutic use , Neovascularization, Pathologic/metabolism , Mice, Inbred C57BL , Melanoma, Experimental/drug therapy , Receptors, Vascular Endothelial Growth Factor/therapeutic use , Angiogenesis Inhibitors/pharmacology , Angiogenesis Inhibitors/therapeutic use , Cell Line, TumorABSTRACT
Metronomic therapy is a therapeutic method in selected oncological diseases, using long-term administration of low doses of drugs with direct or indirect antitumor effect. In addition, to direct cytotoxic eradication of tumor cells, metronomic therapy can very strongly affect the tumor microenvironment; it also has an immunomodulatory and antiangiogenic effect. Its minimal toxic profile allows for use in patients with severe organ dysfunctions and directly impacts the quality of life and social inclusion of oncological patients.
Subject(s)
Antineoplastic Agents , Neoplasms , Angiogenesis Inhibitors/therapeutic use , Antineoplastic Agents/therapeutic use , Humans , Neoplasms/drug therapy , Quality of Life , Tumor MicroenvironmentABSTRACT
The seeds of Euphorbia lathyris have been used in traditional medicine to treat various medical conditions. However, neither all of their active biocompounds nor the molecular mechanisms underlying their therapeutic effects have been described. A new ethanolic extract of defatted flour from mature seeds of Euphorbia lathyris showed a high total polyphenol content and significant antioxidant activity. Chromatographic analysis showed that esculetin, euphorbetin, gaultherin, and kaempferol-3-rutinoside were the most abundant polyphenolic bioactive compounds. Antiproliferative assays showed a high and selective antitumor activity against colon cancer cell lines (T84 and HCT-15). In addition, a significant antiproliferative activity against glioblastoma multiforme cells was also demonstrated. Its mechanism of action to induce cell death was mediated by the overexpression of caspases 9, 3, and 8, and by activation of autophagy. Interestingly, a reduction in the migration capacity of colon cancer cells and a significant antiangiogenic effect on human umbilical vein endothelial cells were also demonstrated. Finally, the extract significantly reduced the subpopulations of cancer stem cells. This extract could be the basis to develop new therapeutic strategies for the treatment of colon cancer, although further experiments will be necessary to determine its in vivo effects.
Subject(s)
Cell Proliferation/drug effects , Colonic Neoplasms/pathology , Euphorbia/chemistry , Plant Extracts/pharmacology , Seeds/chemistry , Adenocarcinoma/pathology , Antineoplastic Agents, Phytogenic , Antioxidants/analysis , Apoptosis/drug effects , Cell Line, Tumor , Colonic Neoplasms/drug therapy , Ethanol , Glioblastoma/pathology , Human Umbilical Vein Endothelial Cells , Humans , Neovascularization, Physiologic/drug effects , Plant Extracts/therapeutic use , Polyphenols/analysisABSTRACT
Neurovespina is a synthetic peptide modified from Occidentalin-1202, a nine amino acid residue peptide isolated from the venom of the social wasp Polybia occidentalis. Previous studies showed that this peptide has a neuroprotective effect on the central nervous system, but its action on the eye has not been explored. So, the objective of this work was to investigate the neuroprotective effect of Neurovespina on the retina and its angiogenic potential in the chicken chorioallantoic membrane (CAM). Retinal ischemia was induced in rats by acute elevation of intraocular pressure (IOP). Electroretinography (ERG) measurements, histopathological and immunohistochemical analysis, and transmission electronic microscopy (TEM) records were performed to check the neuroprotection effect of Neurovespina in the retina of the animals. The angiogenic activity of the peptide was investigated by CAM assay. The results showed that Neurovespina was able to reduce the effects induced by ischemic injury, preventing the reduction of a- and b-waves in the scotopic ERG. Histopathological and immunohistochemistry assays showed that Neurovespina, mainly at 60 µg/ml, protected all layers of the retina. The CAM assay revealed that the peptide promoted the reduction of CAM vessels. So, Neurovespina was able to protect retinal cells from ischemic insult and has an antiangiogenic effect, which can be considered as a promising neuroprotective agent for intravitreal application.
Subject(s)
Ischemia/complications , Neuroprotective Agents/administration & dosage , Retinal Diseases/drug therapy , Retinal Diseases/pathology , Venoms/administration & dosage , Animals , Apoptosis/drug effects , Male , Neovascularization, Pathologic/drug therapy , Rats, Wistar , Retinal Diseases/etiology , Retinal Diseases/physiopathology , WaspsABSTRACT
The plant Moringa oleifera is used as food and medicine. M. oleifera flowers are source of protein, fiber, and antioxidants, and are used to treat inflammation and tumors. This work evaluated the antitumor activity of the M. oleifera flower trypsin inhibitor (MoFTI) in sarcoma 180-bearing mice. Swiss female mice were inoculated with sarcoma 180 cells. Seven days later, the animals were treated intraperitoneally for 1 week with daily doses of PBS (control) or MoFTI (15 or 30 mg/kg). For toxicity assessment, water and food consumption, body and organ weights, histological alterations, and blood hematological and biochemical parameters were measured. Treatment with MoFTI caused pronounced reduction (90.1%-97.9%) in tumor weight. The tumors of treated animals had a reduced number of secondary vessels and lower gauge of the primary vessels compared to the control. No significant changes were observed in water and food consumption or in body and organ weights. Histopathological analysis did not indicate damage to the liver, kidneys, and spleen. In conclusion, MoFTI showed antitumor potential, with no clear evidence of toxicity.
Subject(s)
Antineoplastic Agents, Phytogenic/administration & dosage , Moringa oleifera/chemistry , Plant Extracts/administration & dosage , Sarcoma 180/drug therapy , Trypsin Inhibitors/administration & dosage , Animals , Cell Line, Tumor , Disease Models, Animal , Female , Flowers/chemistry , Humans , Kidney/drug effects , Liver/drug effects , Mice , Oxidative Stress/drug effectsABSTRACT
Advanced clear cell carcinomas originating from both ovaries and kidneys with cancerous peritonitis have poor prognoses. Murine double-minute 2 (MDM2) is a potential therapeutic target for clear cell ovarian carcinomas with WT TP53. Herein, we characterized the antiangiogenic and antitumor effects of the MDM2 inhibitors DS-3032b and DS-5272 in 6 clear cell ovarian carcinoma cell lines and 2 clear cell renal carcinoma cell lines, as well as in clear cell ovarian carcinomas s.c. xenograft and ID8 (murine ovarian cancer cells with WT TP53) cancer peritonitis mouse models. In clear cell ovarian carcinoma s.c. xenograft mouse models, DS-3032b significantly reduced WT TP53 clear cell ovarian carcinoma- and clear cell renal carcinoma-derived tumor volumes. In ID8 mouse models, DS-5272 significantly inhibited ascites production, reduced body weight, and significantly improved overall survival. Additionally, DS-5272 reduced the tumor burden of peritoneal dissemination and decreased CD31+ cells in a dose-dependent manner. Furthermore, DS-5272 significantly decreased vascular endothelial growth factor concentrations in both sera and ascites. Combined therapy with MDM2 inhibitors and everolimus showed synergistic, and dose-reduction potential, for clear cell carcinoma treatment. Our findings suggest that MDM2 inhibitors represent promising molecular targeted therapy for clear cell carcinomas, thereby warranting further studies to evaluate the efficacy and safety of dual MDM2/mTOR inhibitors in clear cell carcinoma patients.
Subject(s)
Carcinoma, Renal Cell/drug therapy , Kidney/drug effects , Ovarian Neoplasms/drug therapy , Proto-Oncogene Proteins c-mdm2/genetics , Adenocarcinoma, Clear Cell/drug therapy , Adenocarcinoma, Clear Cell/genetics , Adenocarcinoma, Clear Cell/pathology , Animals , Apoptosis/drug effects , Carcinoma, Renal Cell/genetics , Carcinoma, Renal Cell/pathology , Cell Cycle/drug effects , Cell Proliferation/drug effects , Disease Models, Animal , Everolimus/pharmacology , Female , Heterografts , Humans , Imidazoles/pharmacology , Kidney/metabolism , Kidney/pathology , Mice , Ovarian Neoplasms/genetics , Ovarian Neoplasms/pathology , Peritonitis/drug therapy , Peritonitis/genetics , Peritonitis/pathology , Platelet Endothelial Cell Adhesion Molecule-1/genetics , Proto-Oncogene Proteins c-mdm2/antagonists & inhibitors , TOR Serine-Threonine Kinases/genetics , Thiazoles/pharmacologyABSTRACT
Among various homing devices, peptides containing the NGR tripeptide sequence represent a promising approach to selectively recognize CD13 receptor isoforms on the surface of tumor cells. They have been successfully used for the delivery of various chemotherapeutic drugs to tumor vessels. Here, we report on the murine plasma stability, in vitro and in vivo antitumor activity of our recently described bioconjugates containing daunorubicin as payload. Furthermore, CD13 expression of KS Kaposi's Sarcoma cell line and HT-29 human colon carcinoma cell line was investigated. Flow cytometry studies confirm the fast cellular uptake resulting in the rapid delivery of the active metabolite Dau = Aoa-Gly-OH to tumor cells. The increased in vitro antitumor effect might be explained by the faster rearrangement from NGR to isoDGR in case of conjugate 2 (Dau = Aoa-GFLGK(c[NleNGRE]-GG)-NH2) in comparison with conjugate 1 (Dau = Aoa-GFLGK(c[KNGRE]-GG)-NH2). Nevertheless, results indicated that both conjugates showed significant effect on inhibition of proliferation in the primary tumor and also on blood vessel formation making them a potential candidate for targeting angiogenesis processes in tumors where CD13 and integrins are involved.
Subject(s)
Antibiotics, Antineoplastic/pharmacology , CD13 Antigens , Daunorubicin/pharmacology , Molecular Targeted Therapy/methods , Neoplasms, Experimental , Oligopeptides/pharmacology , Animals , Cell Proliferation/drug effects , Daunorubicin/analogs & derivatives , Drug Discovery/methods , Humans , Mice , Mice, Inbred BALB C , Mice, SCID , Peptides, Cyclic/pharmacology , Xenograft Model Antitumor AssaysABSTRACT
The growth of adipose tissues is considered angiogenesis-dependent during non-alcoholic fatty liver disease (NAFLD). We have recently reported that our standardized 50% methanolic extract (ME) of Phyllanthus niruri (50% ME of P. niruri) has alleviated NAFLD in Spragueâ»Dawley rats. This study aimed to assess the molecular mechanisms of action, and to further evaluate the antiangiogenic effect of this extract. NAFLD was induced by eight weeks of high-fat diet, and treatment was applied for four weeks. Antiangiogenic activity was assessed by aortic ring assay and by in vitro tests. Our findings demonstrated that the therapeutic effects of 50% ME among NAFLD rats, were associated with a significant increase in serum adiponectin, reduction in the serum levels of RBP4, vaspin, progranulin, TNF-α, IL-6, and significant downregulation of the hepatic gene expression of PPARγ, SLC10A2, and Collα1. Concomitantly, 50% ME of P. niruri has exhibited a potent antiangiogenic activity on ring assay, cell migration, vascular endothelial growth factor (VEGF), and tube formation, without any cytotoxic effect. Together, our findings revealed that the protective effects of P. niruri against NAFLD might be attributed to its antiangiogenic effect, as well as to the regulation of adipocytokines and reducing the expression of adipogenic genes.
Subject(s)
Adipokines/metabolism , Angiogenesis Inhibitors/pharmacology , Angiogenic Proteins/metabolism , Liver/drug effects , Neovascularization, Physiologic/drug effects , Non-alcoholic Fatty Liver Disease/prevention & control , Phyllanthus , Plant Extracts/pharmacology , Adipokines/genetics , Angiogenesis Inhibitors/isolation & purification , Angiogenic Proteins/genetics , Animals , Cell Line , Disease Models, Animal , Gene Expression Regulation , Humans , Liver/metabolism , Liver/pathology , Male , Non-alcoholic Fatty Liver Disease/metabolism , Non-alcoholic Fatty Liver Disease/pathology , Non-alcoholic Fatty Liver Disease/physiopathology , Phyllanthus/chemistry , Plant Extracts/isolation & purification , Rats, Sprague-Dawley , Signal Transduction/drug effectsABSTRACT
Pathological angiogenesis plays a crucial role in malignant neoplasia. Vascular normalization has been confirmed as a promising strategy to promote chemotherapy efficacy. However, compensatory activation of alternative angiogenic receptor tyrosine kinases (RTKs) reduces vascular normalization and induces resistance. Moreover, complexity and heterogeneity of angiogenesis make it difficult to treat with single-target agents. Accordingly, it has been proposed that multiplex inhibition of RTKs could enhance treatment efficacy and overcome resistance on the basis of the vascular normalization concept. Meanwhile, it is feasible to develop multiplex inhibitors against VEGFR-2/Tie-2/EphB4 because of their highly conserved ATP-binding pockets. These inhibitors possess the properties of not only stabilizing the vascular normalization "time window" but also preventing the occurrence of resistance. This novel strategy has yielded promising results in the discovery of antiangiogenic agents. This review highlights the recent progress on the development of such angiogenesis inhibitors.
Subject(s)
Angiogenesis Inhibitors/pharmacology , Protein Kinase Inhibitors/pharmacology , Receptor Protein-Tyrosine Kinases/antagonists & inhibitors , Amino Acid Sequence , Angiogenesis Inducing Agents/pharmacology , Angiogenesis Inhibitors/chemistry , Humans , Neovascularization, Physiologic/drug effects , Protein Kinase Inhibitors/chemistry , Receptor Protein-Tyrosine Kinases/chemistryABSTRACT
Two new triterpenoids (1-2) were isolated and elucidated from the roots of Gypsophila oldhamiana, together with four known triterpenoids (3-6). Their structures were identified to be 3ß-hydroxyolean-13(18)-ene-23, 28-dioic acid (1), 3ß, 12α-dihydroxy-23-carboxyolean-28, 13ß-olide (2), 3ß, 16α-dihydroxy-23-oxoolean-13(18)-en-28-oic acid (3), gypsogenin (4), quillaic acid (5) and gypsogenic acid (6) by spectral methods. All compounds were tested for their cytotoxicities against human tumour cell lines (lung cancer H460 and gastric cancer SGC-7901) and for their antiangiogenic effects using a zebra fish model. All compounds showed interesting antiangiogenic activities and the significant cytotoxicities against H460.
Subject(s)
Caryophyllaceae/chemistry , Triterpenes/analysis , Angiogenesis Inhibitors/pharmacology , Animals , Antineoplastic Agents, Phytogenic/pharmacology , Cell Line, Tumor , Drug Screening Assays, Antitumor , Embryo, Nonmammalian , Humans , Magnetic Resonance Spectroscopy , Oleanolic Acid/analogs & derivatives , Plant Extracts/chemistry , Plant Roots/chemistry , Spectrometry, Mass, Electrospray Ionization , ZebrafishSubject(s)
Angiogenesis Inhibitors/therapeutic use , Carcinoma, Renal Cell/surgery , Kidney Neoplasms/surgery , Stomach Neoplasms/secondary , Aged , Carcinoma, Renal Cell/drug therapy , Endoscopy, Gastrointestinal , Humans , Indoles/therapeutic use , Kidney Neoplasms/drug therapy , Male , Pyrroles/therapeutic use , Stomach Neoplasms/drug therapy , Stomach Neoplasms/pathology , Sunitinib , Treatment OutcomeABSTRACT
PURPOSE: Angiogenesis plays a key role in the growth and metastasis of malignant tumor. Angiogenesis is reportedly enhanced by prostaglandins (PGs). Cyclooxygenase (COX)-2 is an inducible enzyme that catalyzes the formation of PGs from arachidonic acid. The COX enzyme system is composed of two isoenzymes, COX-1 and COX-2. Recent sources of experimental and epidemiological evidence suggest a significant role for the COX enzymes, particularly COX-2, in the pathogenesis of breast cancer. COX-2 overexpression in a murine mammary gland is sufficient to cause tumor formation. We performed our study to determine the effect of COX-2 inhibitor in a in vivo mouse mammary tumor (MMT) cell line. METHODS: In order to test our study, 24 C57BL/6 type mice (Jackson Laboratory, Bar Harbor, USA) were randomized to receive 35 days of either placebo supplemented diet (n=11) or a 1,500ppm celecoxib (CELEBREX, Pfizer Inc. St. Louis, USA) supplemented diet (n=13) beginning at day 0. At 14 days after the beginning day, 30 microliter of a 1% India ink solution that contained 500,000 of MMT cells or dye alone (control) was intradermally inoculated at each flank (day 14). The animals were sacrificed 21 days later (day 35) and skin specimens were harvested/processed for quantification of the microvessel density (MVD) that was associated with each inoculated site. The aortas that were isolated according to each treatment group at the time of animal sacrifice were used to create identical aortic ring angiogenesis assays (media 199 supplemented with 20% FBS). Explants were evaluated for 14 days in culture to determine both the rate of angiogenesis initiation (% of explants exhibiting the angiogenic phenotype) and the neovessel growth rate (using a subjective angiogenic index score for the wells exhibiting initiation). Analysis of variance (ANOVA) was used to evaluate the differences between groups for each assay. RESULTS: According to the immunohistochemical staining, celecoxib administration resulted in a parallel decrease in the MVD at both the control and MMT inoculated sites (22% and 21%, p = 0.025 and p = 0.010 respectively). On the aortic ring assay, the dietary treatment group was not significantly inhibited compared with the placebo group (75% and 63.3%, respectively, p = NS). However, dietary celecoxib administration significantly inhibited the angiogenic index of the neovessel growth rate (5.0 +/- 2.38 and 8.9 +/- 3.44, respectively, p < 0.001). CONCLUSION: These results suggest that a selective COX-2 inhibitor had an antiangiogenic effect on the in vivo tumor cells. We will perform more investigations of a selective COX-2 inhibitors, and these may will be crucial drugs to use as new chemotherapy agents for treating in cancer.
Subject(s)
Animals , Mice , Aorta , Arachidonic Acid , Breast Neoplasms , Celecoxib , Cell Line , Cyclooxygenase 2 Inhibitors , Cyclooxygenase 2 , Diet , Drug Therapy , India , Ink , Isoenzymes , Mammary Glands, Human , Microvessels , Neoplasm Metastasis , Prostaglandin-Endoperoxide Synthases , Prostaglandins , SkinABSTRACT
We investigated the effect of topical application of retimids on the corneal neovascularization in the rat induced by chemical cauterization. The center of corneas of Wistar rats were Cauterized with a silver/potassium nitrate applicator for 5 seconds. And then they were treated topically with 0.1%, 0.2%, 0.5%, 2.0% all-trans retimids (retinol, retinoic acid, retinaldehyde) and dimethyl sulfoxide as a control four times a day. After appiications of eye drops for 5 days, each rat was kined and then perfused with a mixture of 11% gelatin 10% India ink-lactated Ringer's solution. Corneal flat preparation were made, and then the percent of the corneal area occupied by blood vessels were analized by computerized image analyzer. Percent vascularization of 0.1% and 0.2% retnoids were not significantly different from control group(p>0.05). Percent vascu1arization of 0.5% retinaldehyde and all 2.0% retnoids were significantly lower than the contml group(p>0.5). These naturally occurring retinoids were effective in antiarlgiogenesis of rat cornea at relatively high concentrations (>0.5%), when treated topicany, It will be necessary to further study on more potent antiangiogenic, at lower concentration, synthetic retimids for the treatment of angiogenic diseases.
Subject(s)
Animals , Rats , Blood Vessels , Cautery , Cornea , Corneal Neovascularization , Dimethyl Sulfoxide , Gelatin , India , Ophthalmic Solutions , Rats, Wistar , Retinaldehyde , Retinoids , TretinoinABSTRACT
We investigated the effect of topical application of retimids on the corneal neovascularization in the rat induced by chemical cauterization. The center of corneas of Wistar rats were Cauterized with a silver/potassium nitrate applicator for 5 seconds. And then they were treated topically with 0.1%, 0.2%, 0.5%, 2.0% all-trans retimids (retinol, retinoic acid, retinaldehyde) and dimethyl sulfoxide as a control four times a day. After appiications of eye drops for 5 days, each rat was kined and then perfused with a mixture of 11% gelatin 10% India ink-lactated Ringer's solution. Corneal flat preparation were made, and then the percent of the corneal area occupied by blood vessels were analized by computerized image analyzer. Percent vascularization of 0.1% and 0.2% retnoids were not significantly different from control group(p>0.05). Percent vascu1arization of 0.5% retinaldehyde and all 2.0% retnoids were significantly lower than the contml group(p>0.5). These naturally occurring retinoids were effective in antiarlgiogenesis of rat cornea at relatively high concentrations (>0.5%), when treated topicany, It will be necessary to further study on more potent antiangiogenic, at lower concentration, synthetic retimids for the treatment of angiogenic diseases.